Darifenacin Hydrobromide

Pronunciation: DAR-i-FEN-a-sin HYE-droe-BROE-mide
Class: Anticholinergic

Trade Names

Enablex
- Tablets, ER, oral 7.5 mg
- Tablets, ER, oral 15 mg

Pharmacology

Competitive muscarinic receptor antagonist.

Slideshow: How to Manage Your Overactive Bladder

Pharmacokinetics

Absorption

Steady-state plasma levels achieved by day 6 of dosing. Steady-state bioavailability is approximately 15% and 19% for 7.5 and 15 mg doses, respectively. T max is approximately 7 h. Administration with food after a single dose had no effect on AUC, but increased C max by 22% and decreased T max by 3.3 h; no effect was seen on multiple-dose pharmacokinetics. May be administered without regard to meals.

Distribution

Approximately 98% protein bound, primarily to alpha-1 acid glycoprotein. Vd is estimated to be 163 L.

Metabolism

Metabolized by CYP2D6 and CYP3A4. The metabolic products of the hydroxylation and N-dealkylation are unlikely to contribute to the clinical effect. Approximately 7% of white patients and 2% of black patients are poor CYP2D6 metabolizers of the drug, in which case metabolism will be mediated principally by the CYP3A4 isozyme. Individuals with normal CYP2D6 activity are referred to as extensive metabolizers.

Elimination

Approximately 60% eliminated in the urine and 40% in the feces (3% eliminated unchanged). Estimated Cl is 40 L/h and 32 L/h in extensive and poor metabolizers, respectively. Elimination half-life is approximately 13 to 19 h.

Special Populations

Renal Function Impairment

There is no clear relationship between renal function and darifenacin clearance. No dosage adjustment is necessary.

Hepatic Function Impairment

Mild hepatic impairment had no effect on the pharmacokinetics of darifenacin. Unbound darifenacin exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment. Subjects with severe hepatic impairment have not been studied.

Elderly

Cl decreases approximately 6% per decade relative to a median age of 44 y. Exposure at steady state was 12% to 19% higher in subjects 45 to 65 y of age compared with those 18 to 44 y of age.

Children

Pharmacokinetics have not been studied.

Gender

C max and AUC were approximately 57% to 79% and 61% to 73% higher, respectively, in women than in men. No dosage adjustment is necessary.

Race

Effect of race on pharmacokinetics of darifenacin has not been characterized.

Indications and Usage

Treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

Contraindications

Patients with or at risk of urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma.

Dosage and Administration

Adults

PO Start with 7.5 mg once daily. Based on response, dosage may be increased to 15 mg once daily within 2 wk of starting therapy.

Moderate Hepatic Impairment or Coadministered Potent CYP3A4 Inhibitor
Adults

PO A dosage greater than 7.5 mg daily is not recommended.

General Advice

  • Administer with water. Tablet should be swallowed whole and not crushed, chewed, or broken.
  • May be taken with or without food.

Storage/Stability

Store between 59° and 86°F. Protect from light.

Drug Interactions

Anticholinergic agents

Frequency and severity of dry mouth, constipation, blurred vision, and other anticholinergic effects may be increased.

Cimetidine

Darifenacin C max and AUC may be increased. Use with caution and monitor the clinical response to darifenacin.

CYP2D6 inhibitors (eg, duloxetine, fluoxetine, paroxetine, quinidine)

Darifenacin levels may be elevated, increasing darifenacin exposure; however, no dosage adjustments are recommended.

CYP2D6 substrates (eg, flecainide, thioridazine, tricyclic antidepressants [eg, desipramine, imipramine])

Use with caution, especially with drugs with a narrow therapeutic index.

CYP3A4 substrates (eg, midazolam)

CYP3A4 substrate exposure may be increased. This increase is not expected to be clinically important.

Digoxin

Digoxin exposure may be increased slightly. Routine digoxin therapeutic monitoring is warranted.

Moderate CYP3A4 inhibitors (eg, diltiazem, erythromycin, fluconazole, verapamil)

Darifenacin levels may be increased; no dosage adjustments are recommended.

Potassium chloride tablets

The absorption of some coadministered drugs may be altered because of anticholinergic effects on GI motility. All solid dosage forms of potassium chloride are contraindicated in patients receiving darifenacin. The passage of potassium chloride tablets through the GI tract may be delayed. Administration of potassium chloride liquid is a suitable alternative.

Potent CYP3A4 inhibitors (eg, clarithromycin, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir)

Darifenacin plasma concentrations may be elevated by these agents, increasing the pharmacologic and adverse effects. The darifenacin dosage should not exceed 7.5 mg daily when coadministered with potent CYP3A4 inhibitors.

Adverse Reactions

Cardiovascular

Hypertension (1% to 2%); palpitations (postmarketing).

CNS

Headache (7%); asthenia (3%); dizziness (2%); confusion, hallucinations (postmarketing).

Dermatologic

Dry skin, pruritus, rash (1% to 2%).

EENT

Dry eyes (2%); abnormal vision, pharyngitis, rhinitis (1% to 2%).

GI

Dry mouth (35%); constipation (21%); dyspepsia (8%); abdominal pain, nausea (4%); diarrhea (2%); vomiting (1% to 2%).

Genitourinary

UTI (5%); urinary tract disorder, vaginitis (1% to 2%).

Hypersensitivity

Hypersensitivity reactions, including angioedema with airway obstruction (postmarketing).

Metabolic-Nutritional

Weight gain (1% to 2%).

Musculoskeletal

Arthralgia, back pain (1% to 2%).

Respiratory

Bronchitis, sinusitis (1% to 2%).

Miscellaneous

Flu-syndrome (3%); peripheral edema (1% to 2%).

Precautions

Monitor

Identify baseline symptoms (urgency, frequency, incontinence) and monitor patient's response to therapy. Ensure therapy is periodically reviewed to determine if therapy needs to be continued without change, or if a dose change (eg, increase, decrease, discontinuation) is indicated.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Hepatic Function

Use not recommended in patients with severe hepatic impairment.

Angioedema

Angioedema of the face, lips, tongue, and/or larynx has been reported, sometimes occurring after the first dose.

GI motility

Because GI motility may be decreased, use with caution in patients with GI obstructive disorders because of risk of gastric retention, and use with caution in patients with severe constipation, ulcerative colitis, and myasthenia gravis.

Narrow-angle glaucoma

Use with caution and only if benefits outweigh risks in patients being treated for narrow-angle glaucoma.

Urinary retention

Use with caution in patients with clinically significant bladder outflow obstruction.

Overdosage

Symptoms

Severe muscarinic effects.

Patient Information

  • Advise patients to read patient information leaflet before starting therapy and with each refill.
  • Advise patients to take prescribed dose once daily without regard to meals, but to take with food if stomach upset occurs. Advise patient to swallow tablet whole with water and not to crush, chew, or break tablet.
  • Advise patients that dry mouth, constipation, difficulty urinating, and blurred vision are common adverse effects of therapy and to notify their health care provider if any occur and are intolerable.
  • Instruct patients to stop taking the drug and notify their health care provider immediately if any of the following occur: severe abdominal pain, sudden eye pain, inability to urinate.
  • Advise patients that darifenacin can increase the risk of heat prostration and to avoid strenuous activity during periods of high temperature or humidity.
  • Advise patients to take sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
  • Inform patients that medication may cause pupils to dilate, resulting in intolerance to bright lights or sunlight. Advise patient to wear dark glasses to make bright lights or sunlight tolerable.
  • Advise patients that darifenacin may cause dizziness or blurred vision and to use caution while driving or performing other potentially dangerous activities until tolerance has been determined.

Copyright © 2009 Wolters Kluwer Health.

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